This R01 application builds upon a successful R21 grant that examined a cohort of Romanian adolescents and young adults who are long-term HIV survivors and who, despite over a decade of effective treatment, still demonstrate neuropsychological impairments (approx. 50% of subjects). The key feature of the next stage of this study is that these late teens and early 20s HIV+ cases, who were parenterally infected a long time ago, and for whom we have extensive longitudinal biological and treatment information, may experience altered maturation of the brain, with possible neurocognitive and social cognition sequelae. Prior to 1989, only 13 AIDS cases from Romania had been reported to the WHO, while by the end of 1990, 1168 cases were reported, of which 1094 were in children less than 13 years of age. Genetic characterization of the HIV circulating in these institutions revealed that all the children were infected with HIV clade F1 SA#1: Study the neuromedical (NM) characteristics of a long-term surviving cohort of HIV+ patients on HAART and compare them to the HAND features. We will examine the relationship between past and present NM data, including CD4 counts, VL, HAART and HAND-associated elements like: NP impairment, daily functioning, risk behavior, treatment adherence and psychiatric comorbidities. SA#2: Study the viral genetic factors associated with HAND in long-term survivors infected with clade F since early childhood. We will sequence and test in vitro the neurotropic potential of patient viral isolates and identify conserved viral genetic elements ('brain signature sequences') in the env (C2-V3) coding region, from HIV DNA extracted from the CSF and PBMC of subjects with or without HAND. Our study in the well-characterized Romanian cohort offers a unique opportunity to make prognostic correlations between host immune, viral, treatment, comorbid factors, and HAND in young adults who are living with HIV since childhood, most often being infected during the earliest stages of brain development. As these individuals mature, it will be important to understand the implications of neurocognitive impairment on their future behaviors. PUBLIC HEALTH RELEVANCE: Millions of patients are at risk of developing HIV-associated neurocognitive disorders (HAND). We have identified a unique patient cohort that could help in deciphering the risk factors associated with HAND. The overarching hypothesis is that HAND will continue to be prevalent in the long term surviving young adults on HAART and it will have a significant impact on their lives.